Enzyme glutathione conjugation

A biological difference that could increase susceptibility of fetuses and premature or perinatal infants to 1,2-dibromoethane toxicity is developmental immaturity of the P-450 (microsomal enzyme) system. Biotransformation of xenobiotics occurs predominantly by glutathione conjugation (Benet and Sheiner 1985 Sipes and Gandolfi 1986). This pathway is known to generate a number of toxic intermediate metabolites of 1,2-dibromoethane. In addition, fetal mice have selective binding of... 

The conversion of the glutathione conjugate to its cysteinyl derivative is mediated, at least in part, by enzymes in the intestinal epithelial cells. S-(Pentachlorobutadienyl)glutathione and S-(pentachlorobutadienyl)-L-cysteine are partially reabsorbed from the intestines and transported to the liver and subsequently to the body tissues (Gietl et al. 1991). Only a portion of the reabsorbed material is taken up by the liver for additional metabolism. When liver uptake of the glutathione conjugate was measured using perfused rat livers, the maximum uptake observed was 39% (Koob and Dekant 1992). A portion of this material was re-excreted in bile without any metabolic... 

Absorption, Distribution, Metabolism, and Excretion. Data are available on the pharmacokinetics of hexachlorobutadiene in animals by the oral route, but not in humans. There are no data in humans or animals on exposures to hexachlorobutadiene by the inhalation or dermal routes. Because of the key role of the liver in producing the metabolites which are responsible for the nephrotoxicity of this compound, knowledge of the pharmacokinetics of inhalation and dermal exposures would be valuable. Oral studies reported the presence of the enzymes responsible for the glutathione conjugation reaction and the subsequent formation of derivatives in the liver, intestines, and kidney. 

The oxidation of naphthalene was one of the earliest examples of an epoxide as an intermediate in aromatic hydroxylation. The epoxide can rearrange nonenzymatically to yield predominantly 1-naph-thol, interact with the enzyme epoxide hydrolase to yield the dihydrodiol, or interact with glutathione S-transferase to yield the glutathione conjugate, which is ultimately metabolized to a mer-capturic add. 

The further metabolism of suitably stable epoxides may occur, with the formation of dihydrodiols as discussed later. Dihydrodiols may also be further metabolized to catechols. Other products of aromatic hydroxylation via epoxidation are glutathione conjugates. These may be formed by enzymic or nonenzymic means or both, depending on the reactivity of the epoxide in question. 

Is glutathione conjugation the result of a chemical reaction or an enzyme-mediated reaction ... 

Glutathione conjugation can be the result of either an enzyme-mediated reaction or a chemical reaction. 

Phase II Reactions. As with phase I reactions, phase II reactions usually depend on several enzymes with different cofactors and different prosthetic groups and, frequently, different endogenous cosubstrates. All of these many components can depend on nutritional requirements, including vitamins, minerals, amino acids, and others. Mercapturic acid formation can be cited to illustrate the principles involved. The formation of mercapturic acids starts with the formation of glutathione conjugates, reactions catalyzed by the glutathione -transferases. 

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